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REVIEW OPEN A global perspective on the influence of environmental exposures on the

Desire Tshala-Katumbay1,2,3, Jean-Claude Mwanza4, Diane S. Rohlman5,6, Gladys Maestre7 & Reinaldo B. Oriá8

Economic transitions in the era of globalization warrant a fresh look at the neurological risks associated with environmental change. These are driven by industrial expansion, transfer and mobility of goods, climate change and population growth. In these contexts, risk of infectious and non-infectious diseases are shared across geographical boundaries. In low- and middle-income countries, the risk of environmentally mediated brain disease is augmented several fold by lack of infrastructure, poor health and safety regulations, and limited measures for environmental protection. Neurological disorders may occur as a result of direct exposure to chemical and/or non-chemical stressors, including but not limited to, ultrafine particulate matters. Individual sus- ceptibilities to exposure-related diseases are modified by genetic, epigenetic and metagenomic factors. The existence of several uniquely exposed populations, including those in the areas surrounding the Niger Delta or north western Amazon oil operations; those working in poorly regulated environments, such as artisanal industries; or those, mostly in sub-Saharan Africa, re- lying on as a staple food, offers invaluable opportunities to advance the current understanding of brain responses to en- vironmental challenges. Increased awareness of the brain disorders that are prevalent in low- and middle-income countries and investments in capacity for further environmental health-related research are positive steps towards improving human health.

Nature 527, S187-S192 (19 November 2015), DOI: 10.1038/nature16034 This article has not been written or reviewed byNature editors. Nature accepts no responsibility for the accuracy of the information provided.

eports from the World Health Organization (WHO) indicate that scientists and neuroscientists, as well as programme officers at the US the global burden of disease is determined by patterns of disease National Institutes of Health and US National Institute of Environmen- R and disability in low- and middle-income countries (LMICs), tal Health Sciences (NIEHS), and Fogarty International Center. This which, predictably, have their own environmental signatures (http:// Review integrates the goals and approaches to environmental health www.who.int/healthinfo/global_burden_disease/about/en/). How- research as per the NIEHS 2012–2017 strategic plan (https://www. ever, the effect of such signatures on both brain health and region or niehs.nih.gov/about/strategicplan/). global disability-adjusted life years (DALYs) remains unknown and needs to be added to the agenda of global environmental health re- ENVIRONMENTAL EXPOSURE AND BRAIN HEALTH search. As for high-income countries, environmental health research LMICs are home to around 80–85% of the world’s population1. Of these programmes in LMICs must primarily focus on elucidating the entire 5.8 billion people2, 1 billion remain in extreme , living below the range and source of exposures to define the human ‘exposome’ (the US$1.25 per day poverty line3. Around 3 billion people do not have piped measure of all the exposures of an individual in their lifetime and how in their home and 173 million people rely on the direct these exposures relate to health) relevant to brain health in LMICs. The use of surface water. Without proper sanitation, about one billion con- research agenda should also include mechanistic and translational re- tinue to defecate in gutters, in the open bush or in open water bodies4. search, as well as capacity building to foster a new generation of envi- Wildfires and deforestation are commonplace and drought and floods, ronmental health scientists. possibly due to climate change, degrade the existing farming systems and create food insecurity5–7. Armed conflicts and population displace- SCOPE ments impose a toll on human life8. Industrial expansion coexists with In this Review, we focus on environmental risk factors for brain diseases an unprecedented rise in artisanal mining and unprotected labour9. and conditions in LMICs (http://data.worldbank.org/about/country- In some instances, normal urbanization operations, such as road con- and-lending-groups). An iterative search of the literature was con- struction and quarantines (for example during Ebola outbreaks in the ducted using PubMed to retrieve information related to environmental Democratic Republic of the Congo) have created conditions that exac- determinants and mechanisms of brain disease in LMICs. Additional erbated the risk of environmental exposure and brain disease10. Flawed opinion was obtained from interviews with leading environmental regulations compounded by a lack of infrastructure set the stage for

1Department of , Oregon Health & Science University, Portland, Oregon, 97239, USA. 2National Institute of Biomedical Research, 1197 Kinshasa I, Congo. 3Department of Neurology, University of Kinshasa, 825 Kinshasa XI, Congo. 4Department of Ophthalmology, University of North Carolina at Chapel Hill, North Carolina 27599, USA. 5Occupational and Environmental Health, The University of Iowa, Iowa 52242, USA. 6Oregon Institute of Occupational Health Sciences, Oregon Health and Science University, Portland, Oregon, 97239, USA. 7G. H. Sergievsky Center, Columbia University Medical Center, New York, New York 10032, USA. 8Department of Morphology and Institute of Biomedicine, Faculty of Medicine, Federal University of Ceara, Fortaleza 60020, Brazil. Correspondence should be addressed to D. T.-K. e-mail: [email protected].

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Table 1 | Heavy and exposure-related outcomes

Heavy Source of exposure Susceptibility window Neurological outcomes Proposed mechanisms Lead76–78 Lead-contaminated dust, lead-based Lifelong Visual and verbal memory decline, Disruption of paint, soil, drinking water, air, leaded intellectual deficits, decline in release and function, and prenatal gasoline, toys and lead-contaminated executive functioning (fine motor disruption of neuronal migration and sweets function, hand-eye coordination and differentiation; aggravating factors reaction time) and hyperactivity in include poor nutrition (deficiency in children , zinc and calcium) and younger age Mercury79,80 Mining industry, power plants, From neural development to Ataxia in adults and language, Oxidative stress or impairment of crematoria, charcoal industry, and neurulation, and adolescence attention, and visuospatial intracellular calcium and glutamate contaminated food (mostly sea food) performance deficits in children homeostasis and water Arsenic80,81 Contaminated food and drinking 5–15 years Impaired selective and focused Oxidative stress or disruption of water, air and -based attention and long-term memory metabolism of treatments in children, and sensorimotor polyneuropathy Copper82 Contaminated drinking water and Children Alzheimer’s disease, OCD, ADHD, Oxidative stress, microglia food, uncoated copper cookware and Those over 65 antisocial behaviour and anxiety in cell activation or promotion of infant formula containing copper children α-synuclein and fibril formation Cobalt82,83 Contaminated drinking water and Prenatal, young children and the Optic, auditory and peripheral Alteration of mitochondrial oxidative food, inhalation of dust containing elderly neuropathy, motor deficits and verbal phosphorylation or depletion of cobalt particles in various industries memory loss neurotransmitters Cadmium83 Fumes or dust, cigarette smoke, and Prenatal, young children and the Antisocial behaviour and attention Oxidative damage and contaminated food and water elderly impairment in children, parkinsonism neurotransmitter disruption and Manganese76,79 Airborne as fumes, aerosols or Childhood and the elderly Reduced IQ, impaired verbal learning Disruption of mitochondrial suspended particulate matter and and working and immediate memory respiratory chain reaction; contaminated water in children, and Parkinson-like aggravating factors include iron symptoms deficiency and impaired biliary excretion (liver injury or disease) Aluminium84 Contaminated air, water and food, Lifelong Alzheimer’s pathology in the form of Disruption of mitochondrial cosmetics (such as antiperspirants), neurofibrillary tangles respiratory chain reaction or metal industries and pharmaceuticals inflammation; zinc deficiency acknowledged as an aggravating factor

ADHD, attention-deficit hyperactivity disorder; OCD, obsessive compulsive disorder. environmental degradation and pollution to pose serious threats — of a as ), the grass pea sativus or the seeds from the cycad chemical or non-chemical nature — to human health. The degradation plants, which are all known to be associated with a high burden of neu- of local ecosystems leads to the creation of ‘microenvironments’ that rodisabilities at a population level17–22. Populations with unique expo- have a high risk of harmful exposures, often resulting in unique chal- sures and risks include those living in the tropical cassava belt of Ango- lenges and increased risk of human disease (Fig. 1). la, the , Cameroon, Congo, Tanzania, Uganda, Nigeria and Mozambique23–30; those reliant on L. sativus as a staple food HIGH-RISK POPULATIONS AND MICROENVIRONMENTS in Ethiopia, Eritrea, and Bangladesh20,31–33; and the people of the Risk of exposure-related brain disease is determined by age, gender Pacific island Guam or the Japanese Kii Peninsula where the rates of and microenvironments created by natural disasters in which eco- environmentally linked syndromes such as amyotrophic lateral sclero- nomic, social and cultural determinants of health often have impor- sis-parkinsonism-dementia complex (ALS/PDC) have been declining tant roles. One example of a profit-mediated environmental risk is that for reasons that have yet to be uncovered34,35. caused by the oil industry through accidental spills or mismanagement The impact of early childhood diseases that lead to a vicious cycle of of oil operations. For instance, crude oil operations have polluted large enteric infections and has been underestimated and ne- areas of rainforests, including streams and rivers in Ecuador, Peru glected, especially in areas that lack acceptable levels of hygiene and and Colombia11. The population of Nigeria has faced similar challenges sanitation and that have reduced accessibility to vaccines and antimi- owing to reoccurring oil spills as a result of ageing, ill-maintained or crobials. This has caused clinically silent, chronic-illness-related ef- sabotaged pipelines in the Niger Delta. The impact of such man-made fects, which jeopardize the child’s full cognitive development13,15. This and preventable natural disasters on human health has yet to be deter- vicious cycle establishes what is called environmental enteropathy, a mined. Effects on human health will depend on the type and composi- mostly subclinical condition (even without diarrhoea) caused by var- tion of the spilled oils, which often contain a mixture of polycyclic hy- ious degrees of intestinal barrier dysfunction, luminal-to- in- drocarbons that are known to be toxic to the nervous system11. Oil spills testinal bacterial translocation, low-grade local and systemic inflam- arise owing to reasons, such as a lack of vigilance, neglect of necessary mation, and disrupted innate intestinal immune responses that may health and safety checks, or sometimes even promotion of commercial affect growth36 and cognition37 and possibly lead to neurodegeneration interests at the expense of communities. Symptoms of acute exposure as well as liver, and metabolic diseases later in life38,39. to raw oil include consistent episodes of , nausea, dizziness Adolescents in LMICs experience a higher burden of exposures (in and fatigue. Chronic effects include psychological disorders, endocrine contrast with those in high-income countries), primarily because of abnormalities and genotoxic effects12. the childhood labour crisis. Although there are regulations and inter- Microenvironments in which the population has a higher suscep- national agreements restricting child labour, often there are exceptions tibility to exposure-related diseases have also been created by extreme for certain industries, notably the growing agricultural industry, one poverty and natural disasters, including drought and flooding that can of the most hazardous industries worldwide40,41. In this context, ado- degrade soils, plants and farming operations. The burden of conven- lescent workers are at risk of exposure to agrochemicals such as pesti- tional neurodevelopmental stressors (for example, lead) on children cides42,43. Other work-related threats include exposure to organic sol- is exacerbated by unique environmental challenges, including mal- vents in work that involves painting and manufacture, to toxic metals nutrition and enteric infections13–16 and, possibly, a diet of neurotoxi- and fine particulate matters in artisanal mining, and to heat and am- cant-containing plants such as cassava (Manihot esculenta; also known bient air pollution while working long hours and outside41. Exposure to

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Table 2 | Organic compounds and exposure-related outcomes

Organic compound Source of exposure Susceptibility window Neurological outcomes Proposed mechanisms Bisphenol A85,86 Food from cans with linings that Prenatal and childhood Anxious behaviour, hyperactivity and Unclear, but females seem to be more contain BPA, and contaminated food depressive behaviour, and learning susceptible and water impairment in children Phthalates86–88 Food or drink that has been in Prenatal and childhood Depressive and conduct-related Oxidative stress contact with containers or products behaviours (ODD, attention containing phthalates, and air and problems, rule-breaking and dust containing phthalates aggressive behaviour in children) Organophosphates89,90 Contaminated food and water, Lifelong Neurodevelopmental deficits, Inhibition of acetyl-cholinesterase polluted air and professional dermal impaired attention and working contact memory, impaired speed and executive functions, and delayed peripheral polyneuropathy Organochlorinated compounds Contaminated food, drinking water Prenatal and lifelong Impaired intellectual ability, ADHD- Disruption of neurotransmitter (DDT/PCBs)91 and air like behaviours and locomotor function, oxidative stress deficits or derangement of calcium homeostasis; children seem to be more susceptible. Organobromide compounds Contaminated food, water and air Lifelong IQ deficits, impaired attention, fine Impairment of thyroid hormone (PBDEs)92,93 motor coordination and cognition homeostasis functioning in children Organic solvents94,95 Air and professional dermal contact Adolescence and adulthood Headache, memory deficits, and adduction and/or oxidative and glue sniffing central and peripheral neuropathy misfolding or oxidative stress Food-born neurotoxicants Oral ingestion Lifelong Spastic paraparesis, cognition deficits Oxidative stress, excitotoxicity and (cassava cyanogenic glucosides and possibly convulsive disorders protein carbamylation for cassava and BOAA in Lathyrus cyanogens; children and females 96–98 seem to be more susceptible; sativus) or contaminants malnutrition is acknowledged as an (fungal ) aggravating factor

ADHD, attention-deficit hyperactivity disorder; BOAA, beta-(n)-oxalyl-amino-l-alanine acid; BPA, bisphenol A; DDT/PCBs, dichlorodiphenyltrichloroethane/polychlorinated biphenols; ODD, oppositional defiant disorder.

Table 3 | Complex exposures and neurological outcomes

Exposure Source of exposure Susceptibility window Neurological outcomes Proposed mechanisms Coal/charcoal burning99,100 Charcoal/coal combustion, gas Lifelong Neurological signs of exposure to Oxidative stress grilling, wood smoke, or coal mine arsenic dust or ash Car emissions101,102 Contaminated air Lifelong Learning disability and motor Oxidative stress or neurotransmission impairment disruption Fine and ultrafine particulate Air pollution from car or construction Lifelong Behavioural and decreased IQ, Oxidative stress, neurotransmission matters103 equipment exhausts, wood burning, impaired fluid cognition, memory disruption or neuroinflammation heating oil or coal, forest fires, and executive functions, and possibly volcanic eruptions, tobacco smoke autism and cooking industrial solvents such as n-hexane, for example, may occur because occur under the conceptual framework shown in Fig. 1. Chemicals with of poor safety regulations or recreational glue sniffing. This may result neurotoxic potential that people are commonly exposed to are listed in headache, acute or sensorimotor neuropathies that in Tables 1–3. Mixed exposure, for example chemical-covered FUPM are reversible on cessation44. from industrial emissions; co-exposure to chemical and non-chemi- Adults in LMICs may be at a particularly high risk of environmental cal stressors; and repeated and multiple exposure can occur, creating a exposure and related brain diseases compared with those in high-in- complex human environmental exposome. come countries. In general, they experience a higher burden of disease Brain damage linked to chemical exposure may result from chem- owing to a lifetime of cumulative exposures and co-morbidities that are icals interfering with neurotransmission through molecular mimicry highly prevalent in LMICs. The latter include malaria, nutritional de- or reacting with crucial biomolecules and causing incorrect function ficiencies and neurotropic infections such as those caused by human (for example, protein or DNA adduction and/or crosslinking). For T-cell lymphotropic viruses (HTLV). For example, it was reported that both chemical and non-chemical exposures, the mechanisms of brain endemic foci of HTLV-I-associated myelopathy coexist with outbreaks damage may include injury to the vascular system (for example, fine of (a spastic paraparesis linked to the of cassava cyano- particulate matter induced vascular pathology), systemic dyshomeo- gens) in some regions of the Congo45,46. In these areas, women of child- stasis (for example, cadmium-induced kidney disease) and hormonal bearing age are particularly susceptible to the toxicity of cassava cyano- imbalance (for example, through endocrine disruption; Table 1). gens for reasons that have not been elucidated, although they may be The susceptibility to exposure-related disease is, however, de- linked to hormonal influences and poor nutrition47. termined by mechanisms of functional genetics, epigenetics and metagenomics at the interface between risk factors and neurological PATHWAYS TO BRAIN DISEASE outcomes (Fig. 2). Exposure-related brain damage may result from chemical and/or It is increasingly acknowledged that genetic and epigenetic factors, non-chemical stressors. Damage to the nervous system often leads including the effect of maternal stress on brain function, influence the to a range of bilateral and symmetrical motor and/or sensory symp- effect of environmental exposure48,49. For example, the E4 allele of the toms. Behavioural problems, cognition deficits and psychiatric illness APOE gene that is reportedly associated with higher risk of late-onset may also occur. Non-chemical stressors include, but are not limited to, Alzheimer’s disease, although not in people from sub-Saharan Africa psychological stress, heat, noise, fine and ultrafine particulate matter and with a mild association among Hispanic people, is associated with (FUPM), and waterborne, airborne or foodborne pathogens that may protection against early childhood diarrhoea and its related cognitive

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Figure 1 | Environmental (chemical and non-chemical) threats to brain health in low- and middle-income countries. Multiple sources of exposure (air, water and food) coexist, and malnutrition and vector-borne diseases, notably infections, compound the risk of brain disease. Co-exposures not shown include heat, psycho- logical stress and a poor physical environment, such as crowding. impairment50–52. One example of gene–environment interactions is the associated with environmental exposures. The existence of uniquely relationship between air pollution components and the gene encod- exposed populations in LMICs offers invaluable opportunities to ad- ing the MET receptor tyrosine kinase. Several studies have implicated vance our current understanding of brain responses to environmental MET as an autism risk gene53–55. Stratification of the risk conferred by a threats. In some instances, well-characterized neurotoxicants may be functional promoter variant in this gene (rs1858830) and by local traf- used as chemical probes to dissect the pathophysiology of the nerv- fic-related air pollution (regional particulate matter less than 10 mi- ous system. However, challenges at the population level still remain, crometres in diameter and dioxide exposure) revealed signif- including setting exposure limits and developing metrics and meth- icant multiplicative interaction between the risk genotype and the air odologies to assess the long-term impact of environmental exposures pollution exposure56. on disease burden in LMICs and, therefore, globally. Climate change Our knowledge of the pathways that lead to late onset of expo- and mining of rare elements, which may include radioactive materials, sure-related neurological disease is still sparse57,58. Many studies sug- present unpredictable risks, and should be added to the environmental gest that the genetic and environmental causes of late onset diseases health research agenda. The toll of such exposures on the global bur- act in parallel and share common molecular mechanisms59. A number den of disease may be efficiently addressed only through competent of studies have supported the concept that early-life exposure to pol- partnerships and alliances established on a global scale and focused on lutants reprograms global gene expression in old age through epige- key areas and priorities (Box 1). Although there is evidence that some netic mechanisms60–63. Variation in exposure response, even among of these are already in place, more research and research capacity is individuals exposed to the same environment could be due not only needed to continue this agenda to improve human health, globally. to early-life exposures, but also to differences in genetic make up64–66. The extent and nature of exposures and related brain diseases in LMICs ONE HEALTH–GLOBAL HEALTH DIMENSIONS provide opportunities to explore and overcome the long reach that Environmental degradation and contamination, changes in climate and childhood exposure has into adulthood, as well as provide us with new ecosystems, and vector-born pathogens or neurotoxicants are the pri- advances in environmental health sciences67. mary environmental threats to human life and intellectual performance. Exposure-related neurological deficits in LMICs range from pe- ripheral neuropathies to a large number of acute, subacute or chron- ic central nervous system diseases. Deficits may occur prenatally, or BOX 1 | INTERWOVEN RESEARCH AREAS AND IN- during childhood or adolescence, and may be carried through to old VESTMENT PRIORITIES IN GLOBAL ENVIRONMEN- age. Clinical implications include, but are not limited to, neural tube TAL RESEARCH defects, learning disabilities, behavioural problems, psychiatric dis- • Epidemiology and statistical modelling for exposure and risk orders, cognitive decline and the occurrence of distinct entities such assessment in co-exposure and co-morbidity scenarios as , tropical ataxic neuropathy, ALS/PDC and kon- • High-throughput ‘-omic’ methodologies zo20,30,35,68,69 (Fig. 3). • Bioinformatics and knowledge management The human microbiome may be of particular interest to the mech- • Development of diagnostic and remediation tools — validation anistic understanding of exposure-related diseases in LMICs because it and implementation of environmental sensors, detectors and may influence the burden of heavy metals70, the metabolism of food- biomonitors of exposure and related outcomes borne neurotoxicants such as cassava cyanogens18, and the outcome of • Development of metrics and methodologies to assess the long- enteric diseases in early life, including the child’s neurodevelopmental term impact of environmental exposures on neurological disease potential71–73. burden • Understanding the pathways that lead to late onset of exposure- RESEARCH AND CAPACITY BUILDING related neurological diseases Recent advances in environmental health sciences have elucidat- • Training and capacity building in the areas listed above ed the myriad risk factors and mechanisms of brain damage that are

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a b Exposure

Epigenetics

Genomics Neurological outcome

Metagenomics

Co-morbidity

Figure 2 | Environmental framework and pathways to environmentally induced Figure 3 | Neurocognition deficits in konzo, a disease linked to eating cyano- neurological disease in low- and middle-income countries. Susceptibility to genic cassava. a, in a 14-year old boy severely affected by konzo.b , neurological disease is determined at the interface between a particular expo- Deficits in mental processing are evident from the results of a neuropsycho- sure, epigenetic and metagenetic make up, and the presence of co-morbidities. logical test.

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Toxic metals and oxidative stress part This work is licensed under the Creative Commons Attribution 4.0 I: mechanisms involved in metal-induced oxidative damage. Curr. Top. Med. Chem. International License. The images or other third party material in this 1, 529–539 (2001). article are included in the article’s Creative Commons license, unless 81. Florea, A. M. & Busselberg, D. Occurrence, use and potential toxic effects of metals indicated otherwise in the credit line; if the material is not included under the Creative and metal compounds. Biometals 19, 419–427 (2006). Commons license, users will need to obtain permission from the license holder to repro- 82. Valko, M., Morris, H. & Cronin, M. T. Metals, toxicity and oxidative stress. Curr. Med. duce the material. To view a copy of this license, visit http://creativecommons.org/ Chem. 12, 1161–1208 (2005). licenses/by/4.0

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